Optical coupler for in vivo examination of biological tissue

ABSTRACT

For in vivo examination using a spectrophotometer that generates optical radiation and characterizes biological tissue by detecting photons that have migrated in the tissue, an array of optical fibers that transmit radiation between the spectrophotometer and biological tissue, the fibers including distal ends freely protruding from a support in the manner of bristles from a hairbrush, forming an array of optical ports to couple photons to a contiguous tissue region or to collect photons from the tissue region, the optical fibers including proximal ends arranged to optically couple the radiation with the spectrophotometer. Also shown are: fibers sized and distributed to penetrate freely extending hair on the subject&#39;s head to make optical contact over an array of points with the scalp or skin; the array of fibers constructed as a handheld probe moved and placed against the head; optical matching material coupling between the fibers and the biological tissue region; and an irradiation array with the proximal fiber ends coupled to a light source, e.g. for brain tissue examination. Also shown are fibers as a detection array, e.g. for brain tissue examination or for imaging of the brain or for use in a magnet used for magnetic resonance imaging. The spectrophotometer is shown as a continuous wave spectrophotometer, phase modulation spectrophotometer, time resolved spectrophotometer and a phased array spectrophotometer.

This is a continuation of pending International Patent Application No.PCT/US96/00235, with an international filing date of Jan. 2, 1996, whichis a continuation-in-part of U.S. application Ser. No. 08/367,939 nowU.S. Pat. No. 5,596,987, filed Jan. 3, 1995.

BACKGROUND OF THE INVENTION

Continuous wave (CW) spectrophotometers have been widely used todetermine in vivo concentration of an optically absorbing pigment (e.g.,hemoglobin, oxyhemoglobin) in biological tissue. The CWspectrophotometers, for example, in pulse oximetry introduce light intoa finger or the ear lobe to measure the light attenuation and thenevaluate the concentration based on the Beer Lambert equation ormodified Beer Lambert absorbance equation. The Beer Lambert equation (1)describes the relationship between the concentration of an absorbentconstituent (C), the extinction coefficient (ε), the photon migrationpathlength <L>, and the attenuated light intensity (I/I_(o)). ##EQU1##However, direct application of the Beer Lambert equation poses severalproblems. Since the tissue structure and physiology vary significantly,the optical pathlength of migrating photons also varies significantlyand can not be simply determined from geometrical position of a sourceand detector. In addition, the photon migration pathlength itself is afunction of the relative concentration of absorbing constituents. As aresult, the pathlength through an organ with high blood hemoglobinconcentration, for example, will be different from the same with a lowblood hemoglobin concentration. Furthermore, the pathlength isfrequently dependent upon the wavelength of the light since theabsorption coefficient of many tissue constituents is wavelengthdependent. One solution to this problem is to determine ε, C, and <L> atthe same time, but this is not possible with the pulse oximeters knownpreviously.

Furthermore, for quantitative measurement of tissue of a small volume(e.g., a finger) photon escape introduces a significant error since thephotons escaped from the tissue are counted as absorbed. Other errorsmay occur due to irregular coupling of light to the examined tissue orvarying relative geometry of the input and detection ports.

The time resolved (TRS-pulse) and phase modulation (PMS)spectrophotometers can measure the average pathlength of migratingphotons directly, but the proper quantitation of the time resolved orfrequency resolved spectra can be performed only when the spectra arecollected at a relatively large source-detector separation. Thisseparation is difficult to achieve for a small volume of tissue such asthe earlobe, a finger or a biopsy tissue.

Therefore, there is a need for a optical coupler used with aspectrophotometric system and method that quantitatively examines arelatively small volume of biological tissue.

SUMMARY OF THE INVENTION

The invention features a spectrophotometric system for examination of arelatively small volume of biological tissue of interest using visibleor infra-red radiation.

According to one aspect of the invention, a spectrophotometric systemfor examination of a relatively small object of interest (e.g.,biological tissue, organic or inorganic substance in a solid, liquid orgaseous state) using visible or infra-red radiation introduced to a pathpassing through the object. The system includes a spectrophotometer withan optical input port adapted to introduce radiation into the object andan optical detection port adapted to detect radiation that has migratedthrough a path in the object, photon escape preventing means arrangedaround the relatively small object of interest and adapted to limitescape of the introduced photons outside the object, and processingmeans adapted to determine an optical property of the object based onthe changes between the introduced and the detected radiation.

According to another aspect of the invention, a system for examinationof a relatively small volume of biological tissue of interest usingvisible or infra-red radiation includes a spectrophotometer with a lightsource adapted to introduce radiation at an optical input port, adetector adapted to detect radiation that has migrated through a pathfrom the input port to an optical detection port, and a processoradapted to evaluate changes between the introduced and the detectedradiation. The system also includes an optical medium of a relativelylarge volume, forming photon preventing means, having selectablescattering and absorptive properties, positioning means adapted tolocate the biological tissue of interest into the migration path tocreate a tissue-medium optical path, the optical medium substantiallylimiting escape of photons from the tissue-medium optical path, andprocessing means adapted to determine a physiological property of thetissue based on the detected optical property of the tissue-mediumoptical path and the scattering or absorptive properties of the opticalmedium.

Preferred embodiments of these aspects of the invention include one ormore of the following features.

The photon escape preventing means include an optical medium of aselectable optical property surrounding the object. The selectableoptical property is an absorption or scattering coefficient.

The photon escape preventing means include an optical medium surroundingthe object; the medium has at least one optical property substantiallymatched to the optical property of the object.

The spectrophotometer is a continuous wave spectrophotometer (CWS) asdescribed in PCT applications WO 92/20273 and PCT/US95/15666, a phasemodulation spectroscopic unit (PMS) as described in U.S. Pat. Nos.4,972,331, 5,187,672, or a PCT application WO 94/21173, time resolvedspectroscopic (TRS) unit as described in U.S. Pat. Nos. 5,119,815 or5,386,827 or a PCT application WO 94/22361, or a phased array system asdescribed in WO 93/25145, all of which are incorporated by reference asif set forth in their entireties herein.

The determined physiological property is the hemoglobin saturation, theconcentration of an enzyme or the concentration of a tissue substancesuch as glucose.

The system performs a single measurement or a continuous, time-dependentmonitoring of the selected physiological property.

The above-described system operates by introducing into the object,surrounded by the photon escape preventing means, electromagneticradiation of a selected wavelength and detecting radiation that hasmigrated in the object from the input port to the optical detectionport. The system determines an optical property of the object based onthe changes between the introduced and the detected radiation. Inaddition, different photon escape preventing means having a surroundingoptical medium with the optical property comparable to the opticalproperty of the object may be selected. Then, the system measures againthe optical property of the object. The measurements may be repeatediteratively until the optical property of the surrounding medium issubstantially matched to the optical property of the object.

According to another important aspect, the invention is an opticalcoupling system for non-invasively monitoring a region of living tissue.The coupling system includes an excitation (input) port positionable atthe tissue and adapted to introduce optical radiation into the monitoredtissue, a first light guide defining an excitation channel for conveyingthe radiation from a source to the excitation port, and a detectionport, positionable at the tissue, adapted to receive radiation that hasmigrated in the monitored tissue from the excitation port to thedetection port. The detection port has a detection area larger than ainput area of the excitation port. Connected to the detection port is adetecting light guide, for conveying the radiation from the detectionport to an optical detector. The coupling system also includes opticalmatching fluid contained within a flexible optically transparent bag anddisposed partially around the monitored tissue and the excitation anddetection ports.

Preferred embodiments of this aspect of the invention includes one ormore of the following features.

The optical coupling system may include multiple excitation (input)ports positionable at the tissue and adapted to introduce radiation ofthe source into the monitored tissue, and multiple light guides, eachdefining an excitation channel for conveying the radiation from thesource to the corresponding excitation port.

The optical coupling system may also include multiple detection portspositionable at the tissue and adapted to receive radiation that hasmigrated in the monitored tissue, and multiple detecting light guideseach connected to the corresponding detection port for conveying theradiation from the detection port to at least one optical detector.

The optical matching fluid may be positioned partially between the portsand the monitored tissue. The optical matching fluid may have knownscattering or absorptive properties.

The optical coupling system may further include means for changingscattering or absorptive properties of the optical matching fluid andmeans for calibrating the coupling system by controllably changingscattering or absorptive properties of the optical matching fluid.

According to another important aspect, the invention is an opticalcoupler for in vivo examination of biological tissue. The opticalcoupler includes an optical input port of a selected input areapositionable on or near the examined tissue, a first light guideoptically coupled to the optical input port and constructed to transmitoptical radiation of a visible or infra-red wavelength from a source tothe optical input port, wherein the optical input port is constructedand arranged to introduce the optical radiation to the examined tissue,and an optical detection port of a selected detection area positionableon or near the examined tissue. The detection port is constructed andarranged to receive radiation that has migrated in the examined tissuefrom the input port to the detection port. Optically coupled to thedetection port is a detector light guide constructed to transmit theradiation from the detection port to an optical detector. The opticalcoupler also includes optical medium disposed at least partially aroundthe examined tissue and the input and detection ports and constructed tolimit escape of, or account for photons escaped from the examinedtissue.

According to another important aspect, the invention is an opticalcoupler for in vivo examination of biological tissue. The opticalcoupler includes an optical input port of a selected input area directedtoward the examined tissue, an optical detection port of a selecteddetection area directed toward the examined tissue, and optical mediumdisposed at least partially around the examined tissue and the input anddetection ports. The optical medium is also placed between the tissueand the input area of the input port and between the tissue and thedetection area of the detection port, and the optical medium exhibitsknown scattering or absorptive properties. Optically coupled to theoptical input port is a first light guide constructed to transmitoptical radiation of a visible or infra-red wavelength from a source tothe optical input port that is constructed and arranged to introduce theradiation to the optical medium. The optical detection port isconstructed and arranged to receive radiation that has migrated in theexamined tissue and the optical medium from the input port to thedetection port. Optically coupled to the detection port is a detectorlight guide constructed to transmit the radiation from the detectionport to an optical detector.

According to another important aspect, the invention is an opticalcoupling system for non-invasively monitoring a region of biologicaltissue. The coupling system includes a source probe made of at least twooptical fibers having distal ends positionable directly at the tissue.Each distal end forms an input port constructed to introduce opticalradiation into the examined tissue. The fibers have proximal endsconstructed and arranged to form at least one coupling port forreceiving the radiation from a source. The coupling system also includesa detection probe made of at least one optical fiber having a distal endpositionable directly at the tissue. The distal end forms a detectionport constructed to receive radiation that has migrated in the examinedtissue. The fiber has a proximal end constructed and arranged to form atleast one coupling port for conveying the detected radiation to anoptical detector.

The optical fibers may include at the input port or at the detectionport an optical matching medium arranged to achieve a desired couplingof the radiation.

Preferred embodiments of this aspect of the invention includes one ormore of the following features.

The optical medium may have absorptive or scattering propertiessubstantially matched to the absorptive or scattering properties of theexamined tissue.

The optical coupler may further include an optical system constructedand arranged to alter controllably absorptive or scattering propertiesof the optical medium. The system may be adapted to substantially matchthe absorptive or scattering properties of the optical medium to theabsorptive or scattering properties of the examined tissue.

The optical coupler may further include a second input port of aselected input area, and a light guide optically coupled to the secondinput port. The detection port may be placed symmetrically relative tothe first input port and the second input port. The detection port maybe arranged in a transmission geometry or in a backscattering geometryrelative to the input ports.

The optical coupler may accommodate movable optical ports relative tothe examined tissue.

The optical coupler may further include multiple input ports, andmultiple light guides optically coupled to the corresponding inputports. The multiple input ports may be arranged to introducesimultaneously radiation of known time varying pattern to form resultingintroduced radiation possessing a substantial gradient of photon densityin at least one direction. The multiple input ports may form a onedimensional or two dimensional array. The optical detection port may bemovable to another location relative to the examined tissue.

The optical coupler may also include multiple detection ports, andmultiple detector light guides optically coupled to the correspondingdetection ports.

The optical medium may be made of a solid, liquid, or gas. The opticalmedium may also include solid particles of smooth, spherical surface, orstyrofoam. The optical medium may also include a liquid of selectablescattering or absorptive properties such as an intralipid solution. Theoptical medium may include a pliable solid of selectable scattering orabsorptive properties.

The optical coupler may have the detection area of the optical detectionport is larger than the input area of said optical input port.

The optical coupler may further include a port for the needlelocalization procedure or may be arranged for ultrasonic examination ofthe tissue performed simultaneously with, or subsequently to the opticalexamination of the tissue. The optical coupler may further include a setof MRI coils arranged to perform an MRI examination of the tissue.

The optical coupler may be disposed on an endoscope, catheter, guidewireor the like for insertion via a body passage, or transcutaneously, tointernal tissue. The optical coupler is designed for visual andspectroscopic examination the selected internal tissue. The catheter mayinclude an inflatable balloon that can press the input and detectionports against the tissue selected for spectroscopic examination. Thecatheter may also include a biopsy attachment for taking a biopsyspecimen from a tissue region before or after the spectroscopicexamination.

According to another important aspect, the invention is an opticalcoupler for in vivo examination of biological tissue. The opticalcoupler includes an optical input port of a first selected area directedtoward the examined tissue and a second selected area oppositelyoriented to the first area, and an optical detection port of a selecteddetection area directed toward the examined tissue. The input port isconstructed to accept a light beam scanned over the second area andintroduce the beam to the tissue at the first area. The optical coupleralso includes optical medium disposed at least partially around theexamined tissue and the input and detection ports. The optical medium isalso placed between the tissue and the input area of the input port andbetween the tissue and the detection area of the detection port. Theoptical medium exhibits known scattering or absorptive properties. Theoptical detection port is constructed and arranged to receive radiationthat has migrated in the examined tissue and the optical medium from theinput port to the detection port. Optically coupled to the detectionport is a detector light guide constructed to transmit the radiationfrom the detection port to an optical detector.

Preferred embodiments of this aspect of the invention includes one ormore of the following features.

The detection area of the optical detection port may include amultiplicity of detection subareas located at a known position of thedetection area. Each detection subarea is constructed and arranged toreceive radiation that has migrated in the examined tissue and conveythe received radiation to a detector.

The optical detector may include an array of semiconducting detectorseach receiving light from a corresponding detection subarea via thedetector light guide. Thus a time profile of the detected radiation canbe measured at the individual locations.

The light beam may be scanned over the input port using a selectedpattern relative to a detection sequence accumulated over the detectionsubareas. Then, by knowing the input and detection locations of themigrating photons, average photon migration paths may be calculated.

In general, the optical coupling system provides an excellent couplingof light to the examined tissue. The coupling system may alsosubstantially prevent escape of photons from the tissue surface andachieve semi-infinite boundary conditions for the introduced radiation.A larger volume of optical medium is usually used for a small tissuesize. The optical coupling system also achieves precisely a selectedgeometry of the input (excitation) ports and the detection portsregardless of the tissue shape or property. The precise geometry isfrequently important for proper evaluation of the photon migrationpatterns measured by the continuous wave (CWS) unit, the phasemodulation unit, the TRS unit, or the phased array unit.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a diagrammatic view of a spectrophotometric system forexamination of tissue of a relatively small dimension.

FIGS. 2 and 2A show different views of a cylinder for preventing escapeof photons during spectrophotometric measurements of a finger.

FIG. 2B shows a set of cylinders of preselected optical properties for afinger oximetry.

FIG. 3 is a diagrammatic view of an optical fiber holder for aspectrophotometric study of the head.

FIG. 4 a plan view of an optical coupling system for monitoring theoxygenation-deoxygenation state of the hemoglobin within the braintissue of a subject.

FIG. 4A depicts an optical coupling system for examination of the braintissue utilizing several input and detection ports.

FIGS. 5 through 5C depict several optical coupling systems for opticalexamination of the breast tissue.

FIG. 5D depicts an optical coupling system with a two dimensional inputarray also adapted for the needle localization procedure.

FIGS. 5E and 5F depict optical coupling systems adapted for opticalexamination together with ultrasound and magnetic resonance imaging,respectively.

FIG. 6 depicts an optical coupling system with optical windows adaptedfor a scanning system with an array detector.

FIGS. 7 and 7A depict a "hairbrush" optical coupling system for opticalexamination of the brain.

FIGS. 8 and 8A depict a "hairbrush" optical coupling system for opticaland MRI examination.

FIGS. 9 and 9A depict a scanning coupling system constructed forexamination of breast tissue.

FIGS. 10, 10A and 10B depict an optical coupler disposed on a catheter.

FIGS. 11 and 11A depict a spectrophotometer disposed on a catheter.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring to FIG. 1, the basic principle of operation of differentoptical couplers is explained by describing a system 10. System 10,designed for examination of biological tissue of a relatively smallvolume, includes an optical medium 12 of selectable optical properties,a spectrophotometer 18, a titrimetric circulation system 30, andcomputer control 35. Biological tissue of interest 14, attached to alocator 15, is immersed in optical medium 12. Spectrophotometer 18examines optical properties of medium 12 by employing visible orinfra-red light conducted via light guides 20 and 22. Light guides 20and 22, which in a preferred embodiment are optical fibers, areconnected to a light source 21 and a light detector 23, respectively.Photons introduced at an optical input port 19 migrate in medium 12through a scattering and absorptive path and are detected at a detectionport 21. The selectable fixed geometry of input port 19 and detectionport 21 controls the migration path, i.e., optical field 25.

System 30 is adapted to change precisely the scattering and absorptiveproperties of medium 12. Medium 12 includes intralipid solution (made byKabi Vitrum, Inc., Clapton, N.C.) that exhibits scattering propertiesdepending on its concentration and carbon black india ink that exhibitsabsorptive properties. The scattering or absorptive properties of medium12 can be either maintained constant and uniform by properly mixing thesolution or can be changed almost continuously by changing theconcentration of the constituents in titration system 30. Tubes 32 and34 are adapted for continuous circulation of the solution.

In system operation, tissue 14 is first located away from optical field25. Spectrophotometer 18 examines medium 12 in field region 25, andcontrol 35 compares the detected data to the preselected values of theabsorption coefficient (μ_(a)) and the scattering coefficient (μ_(s)).Next, locator 15 positions tissue 14 into field 25 and spectrophotometer18 measures the optical properties of tissue 14 and medium 12. From thespectral data collected with and without tissue 14, computer control 35determines the optical properties of tissue 14.

In another preferred method of operation, after measuring the opticalproperties of medium 12, the scattering and absorptive properties ofmedium 12 are matched by titration to the properties of tissue 14 sothat, when inserted into field 25, tissue 14 does not cause perturbationof field 25. After matching the scattering and absorption coefficientsof medium 12 to the coefficients of tissue 14, spectrophotometer 18detects the same data with or without tissue 14. The known titratedvalues of μ_(a) * and μ_(s) * are equal to the μ_(a) and μ_(s) values oftissue 14. The matching process is performed by first matching μ_(a) andthen μ_(s) or vice versa.

The described method is applicable to both in vivo and in vitro tissueexamination. Tissue 14 may be a biopsy specimen enclosed in an opticallytransparent material or a portion of a human finger inserted into medium12. The wavelength of light used by spectrophotometer 18 is selecteddepending on the tissue component of interest (e.g., hemoglobin,oxyhemoglobin, glucose, enzymes); it is within the scope of thisinvention to use multiple wavelengths.

The present invention envisions the use of different preferredembodiments of optical medium 12. Referring to FIG. 2, a hollow cylinder42 filled with medium 12 surrounds, for example, a finger 40 andprevents escape of introduced photons. The optical properties, pressureand volume of medium 12 are controlled by system 30 connected tocylinder 42 by tubes 32 and 34. The inside walls of cylinder 42 are madeof a pliable, optically transparent barrier 44. After insertion intocylinder 42, barrier 44 fits snugly around the finger. The dimension ofinside barrier 44 is such that after finger 40 is withdrawn, medium 12fills the volume of cylinder 42 completely. This enables both abackground measurement of medium 12 and a measurement of finger 40 inmedium 12 in the same way as described in connection with FIG. 1.Optical field 25, controlled by the position of input port 19 anddetection port 21, is either in transmission or reflection geometry.

Referring to FIG. 2B, in another embodiment, cylinder 42 is replaced bya set of cylinders 42A, 42B, 42C . . . , each containing medium 12 in afluid or solid state with a constant preselected absorption andscattering coefficient. The solid optical medium is titanium oxide, orother scatterer, imbedded in an absorbing, pliable medium such as a gel.

A human finger is inserted into the individual cylinders, and theoptical properties of the inserted finger are measured byspectrophotometer 18. Using the known optical properties of thecylinders and the input port-detection port geometry, the opticalproperties (i.e., μ_(a) and μ_(s)) of the finger can be matched to theproperties of one of the cylinders.

The preferred embodiments of spectrophotometer 18 are a continuous wavespectrometer, a phase modulation spectrometer and a time-resolvedspectrometer, all of them described in the above-cited documents.

System 10 operating with a dual wavelength continuous wave spectrometeris used, for example, as a finger oximeter. As shown in FIG. 2A, thevast majority of photons introduced into finger 40 are prevented toescape by surrounding medium 12. Thus, the introduced photons are eitherabsorbed or reach detection port 21 and are registered by the detector.No error of counting the escaped photons as absorbed occurs. Thebackground spectral data corresponding to each selected value of μ_(a) *and μ_(s) * of cylinder 42 are stored in the system that can match thevalues of μ_(a) and μ_(s) of the finger and the cylinder for eachwavelength. For the continuous wave spectrometer that operates at twowavelengths sensitive to hemoglobin (Hb) and oxyhemoglobin (HbO₂) (e.g.,754 nm and 816 nm), the hemoglobin saturation (Y) is calculated bytaking the ratio of absorption coefficients and using the followingequation for the oxygen saturation: ##EQU2## wherein the coefficientsare determined from the extinction values of hemoglobin at 754 nm and816 nm that are ε_(HB) =0.38 cm⁻¹ mM⁻¹, ε_(Hb) =0.18 cm⁻¹ mM⁻¹,respectively, and the difference extinction coefficients betweenoxyhemoglobin and hemoglobin that are Δε_(HbO-Hb) =0.025 cm⁻¹ mM⁻¹ andΔε_(HbO-Hb) =0.03 cm⁻¹ mM⁻¹, respectively.

As known to a person skilled in the art, in the hemoglobin saturationmeasurement the oximeter normalizes the detected data to eliminatefluctuations due to the changing blood volume. However, the volumechanges can be used to detect the pulse rate.

Alternatively, a phase modulation spectrometer is used to measure thephoton migration by detecting the intensity and the phase shift θ ofsinusoidally modulated light introduced at a distance of severalcentimeters from the detector. For tissue of a small volume, the optimaldistance between the input port and the irradiation port is achievedusing optical medium 12. Furthermore, medium 12 substantially eliminatesthe photon escape.

The detected phase shift is directly related to the mean of thedistribution of photon pathlengths shown in FIG. 2A. Photon migrationtheory predicts that the detected photons can be represented by a threedimensional "banana-shaped" distribution pattern in the reflectiongeometry or a "cigar-shaped" distribution pattern in the transmissiongeometry. Inserting tissue 14 into the center of field 25 causesnonuniformities in the distribution of pathlengths, i.e., thebanana-shaped optical field 25 is nonuniform, if the tissue absorptionproperties are different from the properties of medium 12. If μ_(a) ofthe tissue is smaller then that of the surrounding medium, the averagepathlength <L> decreases since photons with longer pathlengths are moreabsorbed and vice versa. Thus, tissue 14 causes changes in thepathlength and the phase shift, θ.

Furthermore, the detected intensity provides a modulation index (M) thatis an important measure of the absorption and scattering properties of astrongly scattering medium. The modulation index is determined as theratio of the AC amplitude (A.sup.λ) to the sum of the AC and DC(DC.sup.λ) amplitude. ##EQU3##

As described in Sevick et al. in Analytical Biochemistry Vol. 195, pp.330-351, 1991, incorporated by reference as if set forth herein, for lowmodulation frequencies (i.e., 2πf<<μ_(a) c) the phase shift is a directmeasure of the mean time of flight, <t>, i.e., θ→2πf<t>. In a mediumwherein all photons travel at a constant speed, c, the phase shiftdescribes the effective, mean pathlength θ→2πf<L>/c. Here, allpathlengths are weighted equally. The determined pathlength is used inBeer-Lambert equation for determination of the absorption properties.

As the modulation frequency increases, the shorter pathlengths becomemore heavily weighted. At frequencies (i.e. 2πf>>μ_(a) c), the phaseshift is no longer a good measure of the distribution of pathlengths andis directly proportional to the absorption coefficient, μ_(a), and theeffective scattering coefficient, (1-g)·μ_(s). ##EQU4## Since theeffective scattering coefficient is wavelength independent, ratio of thephase shifts measured at two wavelengths can be written ##EQU5## whereinθ_(o).sup.λ is the phase shift at the measured wavelength arising fromthe scattering and background absorption. The ratio of the absorptioncoefficients is used, for example, for determination of the tissuesaturation, Y. A dual frequency, dual wavelength phase modulationspectrometer can be used to determine the saturation by eliminatingθ_(o). The ratio of absorption coefficients is expressed as a functionof the phase shifts measured at different frequencies and wavelengths.##EQU6##

Alternatively, a time-resolved spectrometer (TRS-pulse) is employedwhich introduces, at input port 19, pulses of light on the order of lessthan a picosecond. Photons traveling through a distribution of migrationpathlengths 25 are collected at the detection port 21. The intensity ofdetected light in the reflectance geometry, R(ρ,t), (or thetransmittance geometry T(ρ,d,t)) was determined by solving the diffusionequation in an infinite media as a Green's function with near infiniteboundary conditions. Due to the semi-infinite media condition in thereflectance geometry, the separation of the input and output ports mustbe on the order of several centimeters to use the following equation.##EQU7##

For t→∞ the absorption coefficient μ_(a) is determined as ##EQU8##wherein ρ is the separation between input and detection ports and c isspeed of light in the medium. The effective scattering coefficient (1-g)μ_(s) is determined as ##EQU9## wherein t_(max) is the delay time atwhich the detected reflectance time profile (R(ρ,t).tbd.I(t)) reachesmaximum. The right hand side of Eq. 7 is the decay slope of the arrivaltime of the modified pulses. The absorption coefficient is quantified byevaluating the decaying slope of the detected pulse, as described in Eq.7. The effective scattering coefficient, (1-g)·μ_(s), is determined fromEq. 9. For the known μ_(a) and μ_(s) and the input port, output portgeometry, the system has a unique time profile I(t). The stored profileis compared to the time profile detected for the introduced tissue toobtain a difference profile that possesses the scattering and absorptioncoefficients of tissue 14. Alternatively, μ_(a) and μ_(s) of medium 12and tissue 14 are matched by varying the scattering and absorptiveproperties of medium 12 so that the detected time profile is not alteredby introducing tissue 14.

The TRS system can be used to calibrate a CW oximeter to quantify themeasured data. To account for the difference between the geometricdistance (ρ) of the input port and the detection port and the pathlength(<L>), some oximeters use a modified Beer-Lambert equation with adifferential pathlength factor (DPF) as follows:

    absorbance=DPF.ε.[C]                               (10)

However, the differential pathlength factor can not be preciselydetermined by the CW oximeters since it depends on the pathlength. TheTRS determines DPF using the absorption (μ_(a)) and scattering (μ_(s))coefficients as follows: ##EQU10##

Alternatively, a phased array spectrometer, described in WO 93/25145, isemployed to localize a tissue anomaly or image a selected tissue region.

The described systems are constructed to perform either a singlemeasurement or a continuous, time-dependent monitoring of the selectedphysiological property. The may include a visual display for continuousmonitoring of the measured values and may include a alarm that issues awarning signal when the measured value equals to a preselected value.

An alternative embodiment of the optical coupler is an optrode holder 45shown in FIG. 3. Optrode holder 45 is used for examination of the headof a neonate (46). Optical fibers 20 and 22 are projected into a solidscattering material 47, i.e., an escape preventing optical medium, suchas styrofoam, which affords a return pathway for escaping photons 48.The pathlength of the migrating photons in the tissue is much longersince the photons return to the tissue by the scattering materials, asshown by the zig-zag arrows 48. Thus, the banana-shaped pattern willpenetrate more deeply and meaningful spectroscopic data can be obtainedat smaller input-output fiber separations without the danger of photonleakage or "short" by substantially direct pathways. Alternatively, thestyrofoam may be replaced by a metallic foil that reflects back to thetissue radiation of visible or near infrared wavelengths. The foilsurrounds the input and detection ports and the examined tissue.

Referring to FIG. 4, another embodiment is an optical coupling systemthat comprises an optical coupling device 114 and a spacer-coupler 116for coupling the forward end of optical coupling device 114 to the backof the head 110 to monitor a tissue region of the brain. (A similarsystem can monitor other tissue regions, such as internal organs andmuscles.) The spacer-coupler 116 is a thin, flexible, liquid-filled bagthat is inflated by optical matching fluids to the condition depicted.The spacer-coupler 116 also serves as a cushion, providing a softinterface between the forward end of the coupling device 114 and thehead 110.

The optical coupling device 114 comprises a light guide 120 in the formof a bundle of optical fibers constituting an excitation channel forsupplying near red radiation (NR) from the rear of the coupling deviceto head 110. The distal end 121 of the light guide 120 adjacent the head110 forms an excitation port. A detecting light guide 124, which is alsocomprised of optical fibers, extends along the length of the couplingdevice. Surrounding a distal end 125 of detecting light guide 124 is anopaque specular barrier 122. The barrier blocks substantially all directand reflected radiation except that migrating from a region spaced fromthe tissue surface; i.e., barrier 122 acts as an absorber of thenear-surface rays. This enables the connected spectrophotometer todetermine, for example, the oxygenation state of hemoglobin deep withinthe tissue rather than at the surface. To block the leakage of theradiation from the length of the excitation light guide into thedetecting light guide, a thin coating 130 of material substantiallyopaque to the radiation is preferably placed around each of the fiberoptic bundles 120, 124.

The monitoring systems of FIG. 4 can be calibrated by the flowing of amixture of yeast cells and blood of known oxygenation properties throughthe spacer-coupler 116 to determine the ab initio sensitivity of thesystem to oxy-deoxy-hemoglobin solutions of blood. The accuracy of themonitoring system can be improved by compensating for changes of thealbedo of the hair and skin of the subject and also for changes in thethickness of the spacer-coupler 116. Such compensation can be achievedby providing an annulus of optical fibers closely surrounding theexcitation light guide 120, but separated therefrom by an opaquecoating. The excitation radiation supplied through the light guide 120and detected by the annulus of fibers at the forward end of the couplingdevice can be used to monitor the backscattered radiation and alsoregulate the lamp intensity so as to maintain constant incidentradiation.

A similar coupling system is shown in FIG. 4A. The coupling systemincludes a spacer-coupler 116 and two sets of excitation ports 121A,121B, 121C, and detection ports 125A and 125B, each arranged in a row,and a central row of detection ports 126A, 126B and 126C. The input areaof the excitation ports has a diameter of 100 μm to 1 mm and thedetection area of the detection ports has a diameter of 1 mm to 10 mm.The larger detection area is used to increase the collection of themigrating photons. As described above, tubes 32 and 34 are connected toa titration system and used for circulation and controlled opticalchanges of the optical matching fluid contained within a pliable,optically transparent barrier. As described above, the scattering orabsorption properties (μ_(a), μ_(s) ') of the optical medium may beselected to match μ_(a) of the tissue, μ_(s) ' of the tissue or both. Inseveral applications, it is advantageous to match μ_(s) ' and keep μ_(a)very low to substantially eliminate absorption in the optical medium.Thus the absorption coefficient will mainly depend on the properties ofthe examined tissue.

Each row of the excitation ports and the detection ports may be used forindependent examination of the brain tissue by performing a ρ-scan asdescribed in a PCT/US 95/15666, incorporated by reference as if setforth herein. Light guides deliver radiation to individual excitationports 121A, 121B, 121C in sequence and the introduced photons migratethrough the patient's brain to detection ports 125A, 125B over thecorresponding, "banana-shaped" migration paths that depend on theexcitation port--detection port separation. Based on the detected,normalized intensities, the spectrophotometer calculates the values ofμ_(a) and μ_(s) ' that are used to detect a brain bleed, a cerebralhypoxia or tissue plaque characteristic of Alzheimer's disease.

The central row of detection ports 126A, 126B and 126C is used for aseparate phased array measurement described is a PCT/US 95/15694,incorporated by reference as if set forth herein. Light from two sourcesis introduced into the examined brain tissue at excitation ports 121Aand 121A', sequentially. The intensities of the two sources are selectedso that a detection port 126A is located on a null plane of equalintensity in the tissue. A detector detects sequentially radiation thathas migrated from the input ports 121A and 121A' to detection port 126A.The detected signals are stored in a sample-and-hold circuit andsubtracted in a subtraction circuit to create a differential signal. Thedifferential signal is then used to examine the tissue. Thiscancellation measurement is performed over the three sets of excitationand detection ports (i.e., 121A, 121A', and 126A; 121B, 121B', and 126B;121C, 121C', and 126C, respectively) to examine the frontal lobe of thebrain.

Referring to FIG. 5, similar type of the optical coupling system is usedto examine breast tissue 11. A cylindrical optical coupler includes ahollow cylinder 42 filled with optical medium 12. Cylinder 42 is placedover the breast 11 near the chest wall 11A. As described above, theoptical properties, pressure and volume of medium 12 are controlled bysystem 30 connected to cylinder 42 by tubes 32 and 34. The opticalmatching fluid is contained within pliable, optically transparentbarrier 44. The inside walls of cylinder 42 may be coated with a filmthat reflects light in the visible or near infra-red range back to thematching fluid. The optical coupler uses cylinders 42 of different sizesor a cylinder with an adjustable volume so that the coupler can have aselected distance between the breast surface and the inside wall ofcylinder 42. The preferred distance is about 1 centimeter, but for avery small tissue a larger distance is preferable to achievesemi-infinite boundary conditions. Thus the coupler is also useful forexamination of the breast of a small size or after a surgical removal ofthe breast tissue. After placement of cylinder 42, the volume of medium12 is adjusted so that barrier 44 fits snugly around the examinedbreast. Alternatively, the optical medium is a pliable solid, forexample, an absorbing gel containing metallic or oxide sphericalparticles, or silky glass beads as scatterers. When the cylinder isplaced firmly on the examined breast, the excess optical mediumcontained within the pliable barrier is pushed outside of the cylinder.

As described above, spectrophotometer 18 measures the optical propertiesof tissue 11 and medium 12. Light guides 20 and 20A are connected tolight source 21, and light guide 22 is connected to light detector 23.Photons introduced at an optical input ports 19 and 19A migrate inmedium 12 over scattering and absorptive paths and are detected atdetection port 21. The optical medium achieves a uniform coupling oflight to the tissue that is usually pliable and enables preselectedfixed geometry of the input end detection ports. Spectrophotometer 18,which is a continuous wave spectrophotometer, a phase modulationspectrophotometer or time resolved spectrophotometer, evaluates thebreast tissue similarly as described above for the biopsy specimen orthe finger.

Furthermore, the optical resolution may be increased whenspectrophotometer 18 together with the optical coupler are calibrated ona "normal" tissue region and then used to examine another tissue regionthat when "normal" should have the same optical properties as the firsttissue region. For example, the optical coupler is first placed on theleft breast and the optical properties of the tissue are measured. Then,the optical coupler is placed on the right breast suspected to have anabnormal tissue region. The optical properties of the right breast aremeasured and evaluated relative to the optical properties of the normaltissue of the left breast. The relative measurement can be performed bymeasuring the two sets of data independently and subtracting orcomparing them to them to each other. Alternatively, twospectrophotometers, each with an optical coupler placed on one breast,are used simultaneously using a lateralization detector. Such techniqueis described in general (and specifically for examination the brain) ina PCT application WO 92/20273, filed May 18, 1992, incorporated byreference as if set forth herein.

Alternatively, spectrophotometer 18 is a phased array system describedin the PCT/US 95/15694 application cited above. FIG. 5A depicts anoptical coupler for a measurement using a transmission geometry, andFIG. 5B depicts an optical coupler for a measurement using a reflectiongeometry that was already described for coupling system of FIG. 4A. FIG.5C depicts an optical coupler for a phased array system that introducesimultaneously from input ports 19, 19A, 19B and 19C radiation of knowntime varying pattern that form resulting introduced radiation possessinga substantial gradient of photon density in at least one direction. Thedirectional introduced radiation is perturbed by a tissue inhomogeneity(e.g., a tumor, bleeding) and is detected at the detection location 21.Cylinder 42 may include a slit opening to accommodate movement of fiber22 so that detection port 21 may be located at several differentpositions. The tissue is examined or imaged by scanning the introduceddirectional field in two or three dimensions and moving the detectionport over a predetermined geometry, as described in the WO 93/25145document.

A similar optical coupler for a two dimensional phased array system isshown in FIG. 5D. A hollow box 42A filled with optical medium 12contained within a pliable, optically transparent barrier 44 includesseveral optical input ports 19, 19A, 19B, 19C, . . . , arranged to forma two dimensional array, and a slit 49 constructed to receive detectionport 21 of detection fiber 22 or an optical window. Alternatively, port19 can be used as the detection port in a backscattering geometry. Thecoupler may also include a port 50 adapted for the needle localizationprocedure. (If another access is needed, port 19 may be constructed toaccommodate both an optical fiber or the needle.) The inner walls of box42A are lined with a reflecting material that returns photons back tofluid 44. When the coupler is used in the needle localization procedure,the tumor is first identified by X-ray pictures taken through box 42A.While the X-ray pictures are taken, optical fluid 44 may be withdrawn toavoid high attenuation of X-rays. Then, needle 51 is placed through port50 to mark the tumor with a metal wire. The tumor is then examined orlocalized using the two dimensional phased array. Ports 19 or 50 mayalso be used for biopsy of the localized tumor.

Optical couplers used for ultrasound examination and magnetic resonanceimaging in conjunction with the optical spectroscopy are depicted inFIGS. 5E and 5F, respectively. Referring to FIG. 5E, the optical couplerof FIG. 5 includes a port 52 constructed to accept an ultrasound probe.Referring to FIG. 5F, the optical coupler for magnetic resonance imagingis made of non-magnetic materials and includes a set of MRI coils 56located around the tissue. The tissue is imaged by using both MRI andoptical techniques, wherein the image resolution may be increased usingcontrast agents suitable for both MRI and optical examination, asdescribed in the WO 94/22361 application, incorporated by reference asif set forth herein.

Referring to FIG. 6, in another embodiment, the optical coupler includesa set of optical windows instead of the input and detection fibers. Thecoupler includes a hollow cylinder 42A, filled with optical medium 12contained within a pliable barrier, which has three optical windows 63,64A and 64B. A light beam emitted from a light source 62 of aspectrophotometer 60, is directed to a selected location of input port63 by a set of mirrors 68A and 68B and other optical elements. Theoptical system stores the exact position of the input beam relative tothe examined tissue. After migration in tissue 11, the altered light isdetected at detection ports 64A or 64B using a detector 65. Detector 65includes, for example, an array of semiconducting detectors. Opticaldetection ports 64A or 64B are formed from an array of detectionsubareas, and each subarea conveys received radiation to thecorresponding semiconducting detector. Thus, the system can recordintensity and exact co-ordinates of the detected radiation. Based on theknown input radiation and its co-ordinates and detected radiation forthe individual detector locations, the system characterizes the tissueas described in the PCT application WO 93/25145.

Referring to FIG. 7, another embodiment of the optical coupling systemis a hairbrush optical coupler 70. This optical coupler is designed toprovide optimal coupling of light to and from brain tissue in regionswhere the skull is covered by hair. Coupler 70 includes at least onesource probe 72 and at least one detection probe 75. Source probe 72 ismade of approximately twenty optical fibers of 0.5 millimeter to 3millimeter in diameter and at least one half centimeter in length. Inputports 73 (i.e., irradiation tips) of the fibers of source probe 72 arearranged to form a selected structure (e.g., a matrix, mosaic, circularor linear structure) depending on the desired input geometry and thetype of the examined tissue. Each irradiation tip of the fiber mayinclude an optical matching material (e.g., a plastic, a gel-likematerial, a coating or the like) located between the fiber and thetissue and designed to introduce light efficiently into the examinedtissue. At the proximal end, probe 72 has one or more light couplingports 74. The probe has a single light coupling port made of the fibersbundled together and arranged to achieve efficient coupling of lightfrom a light source (e.g., a light bulb, a light emitting diode, alaser) to the probe. Alternatively, the probe has multiple lightcoupling ports (e.g., one port per fiber), wherein the generated lightis coupled into the fibers sequentially or simultaneously.

Detection probe 75 includes one or more detection ports 76 and one ormore light coupling ports 77. Detection probe 75 has a similar design assource probe 72, but may have a larger number of individual fibers inorder to collect a sufficient amount of light that has migrated in thetissue. At the proximal end, the detection fibers may also be bundledtogether to form a single light coupling port 77, which provides goodcoupling to a wide area detector (e.g., a diode detector, a PMT detectoror a MCPD detector). Since source probe 72 and detection probe 75 have asimilar construction, they may be used interchangeably. Several sourceprobes and detection probes may be coupled to an optical sequencer ormultiplexer constructed to transmit and receive light in a desiredmanner. The probes are made of cladded fibers to eliminate crosstalk.

Source probe 72 and detection probe 75 are mounted on a support memberconstructed to achieve a selected position of the fibers and a desiredseparation of the input ports and the detection ports. The supportmember can also transmit pressure to the fiber tips for improvedcoupling of light to the tissue. A connected spectrophotometer (such asa TRS-pulse, PMS, CW, or phased array spectrophotometer) probes deeptissue at large separations of the ports (ρ=5 cm to 10 cm) and probes adermal layer at small separations (ρ=0.5 cm to 2 cm).

The hairbrush optical coupler can be used for examination of symmetricaltissue regions of the brain, breast, arm, leg or other, as is describedin the WO 92/20273 application. The hairbrush optical coupler can bealso employed to detect asymmetrical tissue properties of opticallysymmetrical body regions. FIG. 7A depicts the hairbrush coupler attachedto the head; specifically, to the parietal bones of a newborn whichstill has the characteristic opening called anterior fontanel. Inputports 73A and 73B of source probes 72A and 72B, respectively, arelocated on symmetrical locations of the corresponding parietal bones (orthe temporal bones, the occipital bone, etc.). Detection ports 75A and75B are spaced the same distance (ρ, usually 3 cm to 8 cm) from thecorresponding input ports 73A and 73B. The spectrophotometer introducesradiation of a selected wavelength at each input port and detectsradiation at each detection port. The spectrophotometer stores thedetected data separately and correlates them together or with a storeddata corresponding to the individual brain regions to identify anyasymmetry in tissue properties. Alternatively, the spectrophotometermeasures a differential signal directly. Normal tissue provides asubstantially symmetrical signal. A detected asymmetry may be caused bya tissue disease, such as localized bleeding, an asymmetric strokevolume, or another pathological condition. (For example, see S. P.Gopinath et al., J. Neurosurg., 79, 1993.)

In another embodiment, a multifiber hairbrush probe is used for imagingof the brain. For this purpose, a series of semirigid 1 mm fibers isembedded in a styrofoam or plastic helmet. When the helmet is attachedto the head, the input ports of the fibers project through the hair tothe surface of the scalp. The patient's head is covered by, for example,4 rows of 8 fibers extending from the frontal region to the occipitalregion. A larger number of fibers is used when a higher resolution ofthe image is needed. Each fiber is coupled at its optical coupling portto an optical sequencer or multiplexer. This way any fiber may becoupled to a light source or a light detector of an optical imagerdescribed in PCT/US 93/05868 or PCT/US 95/15694.

Referring to FIG. 8, in another embodiment, the hairbrush opticalcoupler is constructed for in vivo examination of tissue usingsimultaneously magnetic resonance imaging (MRI) and medical opticalimaging (MOI). The coupler includes a styrofoam cap 85 with four rows of8 fibers extending from frontal to occipital region of the patient'shead 88 located inside an MRI magnet 90. The optical fibers extendthrough the hair to the skull and include ferrite caps. Each fiber iscoupled at its optical coupling port to a fiber junction box 92. Fiberjunction box 92, located outside of magnet 90, has appropriateelectromechanical or electro-optical switches to time sequence theswitching of a fiber conduit 91 to any one of the 32 fibers coupled tothe head 88. The system employs any one or more fibers for transmissionand any other fibers for detection. An MRI/MOI control center 94includes an imaging center 95 and a computer system 96, which isconstructed to create and overlay the optical and magnetic images.Coordination of the optical and MRI images is achieved by MRI/opticalmarkers. Three-dimensional markers are formed by coating the fibers witha film exhibiting a magnetically relaxed water-like signal so that eachoptical fiber appears on an NMR image. This way an optical imagegenerated by the corresponding source and detector fibers is correlatedto the MRI image. Importantly, such "labeled" fibers do not interferewith the NMR examination.

Imaging center 95 employs a TRS system described in U.S. Pat. No.5,119,815 or in U.S. Pat. No. 5,386,827. The TRS system includes a Tisapphire tunable laser that generates a series of light pulses ofdifferent wavelengths in the NIR region, sensitive to an endogenous orexogenous pigment. The light pulses, generated as shown in a timingdiagram of FIG. 8A, are transmitted via fiber conduit 91 to fiberjunction box 92. At fiber junction box 92, the signals are multiplexedto the 32 fibers that transmit light to and receive light fromappropriate places in the brain. A single optical fiber may also beconnected to fiber branches which are attached to various places on thehead. The TRS system also includes two 8 multi-anode micro-channel platedetectors. The detector output is send to a parallel computer thatgenerates images congruent with the MRI scan and completed inapproximately the same time as the MRI data.

To achieve proper coupling, the fibers are indexed in space to form anarray and are encoded appropriately by an index pad that mimics thetissue positions. This identifies the position of the fibers in thearray 1 through 32 relative to a master synchronizing pulse. The imagingsequence consists of a series of pulses transmitted through the mainfiber to an identified site at selected intervals (e.g., 5 nanosecond).Each pulse generates a photon migration pattern which is receivedthrough an identified optical coupling fiber and is recognized by thecentral computer as originating from a certain receiving fiber or set ofreceiving fibers by time encoding. The transmitter pulse stimulates alltransmit fibers in sequence. Similarly, the pattern received is acomposite of all receiver positions. The imaging console "knows" notonly the location of the fiber, but also identifies the signal receivedfrom the fiber conduit by its time sequence with respect to thesynchronizing pulse. The transmission/reception algorithm consists of asequence of excitation pulses followed by photon diffusion patternsdetected at the particular positions selected specifically for the organbeing studied.

The system may use a generic transmission/reception algorithm designedfor an average organ or a patient specific algorithm. Furthermore,different algorithms may be used for ipsilateral, contralateral, de novoor recurrent brain bleeding. The optical coupler can be attached to thehead (or any part of the body) for longer periods of time to monitorevolution of a tissue state (e.g., brain bleeding, compartment syndrome,or changes in a stroke induced volume) during and after administrationof a specific drug. For example, the system can also monitor evolutionof a stroke induced volume or changes in intracranial pressure afteradministration of an osmotic agent (e.g., mannitol, glycerol),texamethasone (with its effects delayed for several hours) or anotherdrug that temporarily reduces brain oedema. The system can also monitorevolution of a solute (e.g., glucose) as it equilibrates in thebloodstream.

Computer system 96 provides an overlay of the two images with contrastdue to vascularity/vasculogenesis, blood vessels permeability,proliferation/degeneration of intracellular organelles, or some othertissue characteristics. To properly correlate the optical images to theNMR images, the optical images need to have an adequate contrast. Thedesired gradient of contrast is accomplished by selecting a suitablecontrast agent (i.e., an exogenous pigment) and a wavelength of theintroduced light. The spectrophotometer may construct separate imagesbased on the scattering coefficient or the absorption coefficient.Furthermore, imaging center 95 may employ an amplitude modulation systemor a CW system rather than the TRS system to increase resolution forsome types of images.

Referring to FIGS. 9 and 9A, another embodiment of the optical couplingsystem a scanning coupler 160. Scanning coupler 160, constructed forimaging of breast tissue, employs a spectroscopic imaging systemdescribed in the WO 93/25145 application or in the PCT/US 95/15694application. Scanning system 160 includes an optical coupler 162, whichmay have cubical or cylindrical shape and is filled with optical medium164. Optical coupler 162 is positioned over the breast near the chestwall. As described above, the optical properties, pressure and volume ofmedium 164 may be controlled by an external system connected to thecoupler by a set of tubes. The optical matching fluid (e.g.,twice-diluted J&J baby lotion) is contained within a pliable, opticallytransparent barrier. The inside walls of coupler 162 may be coated witha film that reflects light in the visible or near infra-red range backto the matching fluid to prevent escape of photons from the tissuesurface. The optical coupler may be of different sizes or may have anadjustable volume so that the coupler can have a selected distancebetween the breast surface and the inside walls. (The preferred distanceis about 1 centimeter, but for a very small tissue a larger distance ispreferable to achieve semi-infinite boundary conditions.) Thus thecoupler is also useful for examination of a small breast or after asurgical removal of the breast tissue. After placement of coupler 162,the volume of medium 164 is adjusted so that the barrier fits snuglyaround the examined breast. Alternatively, the optical medium is apliable solid, for example, an absorbing gel containing metallic oroxide spherical particles, silky glass beads as scatterers or a suitableplastic material.

FIG. 9A depicts a set of couplers 162A and 162B for simultaneousscanning of both breasts. Attached to each coupler are source-detectorprobes (168A, 168B, 168C, 168D, 169A, 169B, 169C, 168D), which includeone or more optical sources or detectors described above. The probes aremovable on a rail 170. In an automatic positioning system, each probe isconnected to a servo motor (step motor) that is operated by acontroller. Depending on the spectroscopic system, a fiber 172 (of FIG.9) may be used to collect, at a detection port 174, radiation that hasmigrated in the examined tissue and couple the radiation to a detector.Alternatively, fiber 172 may be used to couple, at input port 174,radiation to the examined tissue.

In an electro-optic scan, a computer controller maintains coordinatedpositions of the probes to the selected combination of the transmittersand receivers. The scan is performed on a single breast orsimultaneously on the contralateral breast. The sensitivity of thesimultaneous scan is increased by measuring a differential signal. Acomputer displays the detected signal or the differential signal in a 3dimensional coordinate system. To increase the resolution, a contrastagent (e.g., cardio-green, indocyanine-green) which is preferentiallyaccumulated in a tumor may by injected intravenously. Several scans areperformed to observe the time dependence of the decay and identify alocation of a suspected anomaly. The system can also calculate thescattering coefficient and absorption coefficient of the suspectedanomaly and the surrounding tissue.

Referring to FIGS. 10 and 10A, in another embodiment, an optical coupler181 is located at a distal end of a catheter 180. Catheter 180 includesat least two optical conduits 184 and 190, which are at the proximal endconnected to a fiber junction box 182 (e.g., a muliplexer, a sequencer).The optical coupler includes at least one input port 186 and at leastone detection port 192, separated by a selected distance, and an opticalbarrier 189 constructed to prevent direct migration of the radiationbetween the ports. Input port 186 and detection port 192 may alsoinclude selected optical medium 188 and 194, respectively. Prior to thespectroscopic examination, optical conduits 184 and 190 may be used forillumination and observation of the internal tissue. At the distal end,catheter 180 may include an inflatable balloon 183. When inflated,balloon 183 presses the optical ports 186 and 192, or pliable opticalmedium 188 and 194 to the examined tissue.

Alternatively, catheter 180 may include, at its distal end, an opticalcoupler 200, shown in FIG. 10B, which is constructed and arranged forexamination or long term monitoring of brain tissue (or another tissue)of a fetus still located in the uterus. Optical coupler 200 includes asuction ring 202 (or a suction cup) constructed to maintain opticalports 204 and 206 at a selected position, and optical medium 194.Catheter 180 is introduced to the uterus either through the birth canalor through the maternal abdominal wall.

Alternatively, optical coupler 200 designed for visual and spectroscopicexamination selected internal tissue, for example, cervix, uterus,gastrointestinal tract, urinary tract, bronchi, and other. Catheter 180is introduced to the selected tissue region via a body passage ortranscutaneously. Optical conduits 184 and 190 are first utilized tolocate, visualize and examine the internal tissue by a clinician. If theclinician locates a tissue region that requires further examination,he/she positions the optical input and detection ports for spectroscopicexamination utilizing a spectrophotometer optically coupled to theproximal end of catheter 180. The spectroscopic examination is performedby detecting back-scattered light that has migrated from the input portto the detection port, or by detecting fluorescent light excited in theexamined tissue. Depending on the type of examination, thespectrophotometer is the above-cited CWS, TRS, PMS or phased arrayspectrophotometer, or a spectrophotometer described in U.S. Pat. Nos.4,930,516, 5,042,494, 5,106,387, 5,131,398, or 5,261,410.

Catheter 180 may also include a biopsy attachment for taking a biopsyspecimen from a tissue region previously examined by thespectrophotometer. The biopsy is performed only if the spectroscopicexamination indicates a potentially abnormal tissue. Thus the initialspectroscopic examination eliminates a substantial number of biopsiesand saves the related cost.

Referring to FIGS. 11 and 11A, in another embodiment, aspectrophotometer is disposed on a catheter 210 (e.g., an endoscopiccatheter), which may include an inflatable balloon 212 and endoscopeoptics 214. The spectrophotometer (e.g., a TRS-pulse, PMS, CW, or phasedarray spectrophotometer) includes light sources 216 and 218 movable ontracks 217 and 219, respectively, and centrally located detectors 220and 222. Optical medium 224 is at least partially surrounding thesources and the detectors. In operation, catheter 210, with the balloondeflated, is passed through a body lumen to the position of interest,guided for example, by fluorimetry or by endoscopic viewing. The balloonis then inflated to press optical medium 224 against the tissue ofinterest. The technique and apparatus may be applied, for example, tobody lumens such as the GI tract (e.g., for measurements of GI trackwall) or to blood vessels, employing an angiographic catheter foranalysis and treatment of occlusions.

A comprehensive system can serve many hospital functions includingtransduction of vital signals from bedside, from the OR, the ICU, or theER to a designated computer. The system may include a large number ofoptrode transducers which may measure all the vital signs (bloodpressure, pulse, temperature, respiration) electrocardiogram,electroencephalogram, serum electrolyte levels, and all the features ofmedical optical imaging (e.g., the simplest detection of hemorrhage,oxygen saturation of hemoglobin, imaging of potential dangers such asstroke, aneurysm rupture, and recurrence of brain bleeding). Thisinformation could be carried by single optical fibers with suitabletransduction to whatever transmission method is optimal including highlysophisticated PCM.

Other embodiment are within the following claims:

I claim:
 1. An optical system for in vivo examination of biologicaltissue, comprisinga spectrophotometer constructed and arranged togenerate optical radiation of at least one visible or infra-redwavelength and to characterize biological tissue by detecting photons ofsaid wavelength that have migrated in the tissue, an array of opticalfibers constructed and arranged to transmit said optical radiationbetween said spectrophotometer and biological tissue, said opticalfibers including distal ends freely protruding from at least one supportin the manner of bristles from a hairbrush and forming an array ofoptical ports constructed and arranged to couple photons of saidradiation to a substantially contiguous tissue region or collect photonsof said radiation from a substantially contiguous tissue region, andsaid optical fibers including proximal ends arranged to optically couplesaid radiation to said spectrophotometer.
 2. The optical system of claim1 wherein said distal ends are sized and distributed to penetrate freelyextending hair on the head of a subject to make optical contact directlyover an array of points with a surface of the scalp or skin below saidhair and near said tissue region.
 3. The optical system of claim 2wherein said array of optical fibers is arranged as an irradiation arraywith said proximal ends optically coupled to a light source of saidspectrophotometer constructed and arranged for brain tissue examination.4. The optical system of claim 2 wherein said array of optical fibers isarranged as a detection array with said proximal ends optically coupledto a light detector of said spectrophotometer constructed and arrangedfor brain tissue examination.
 5. The optical system of claim 2 furtherconstructed for use in a magnet used for magnetic resonance imaging. 6.The optical system of claim 1 wherein said array of optical fibers isconstructed as a handheld probe being sized and configured to be movedand placed against the head.
 7. The optical system of claim 1 whereineach said distal end includes an optical matching material constructedand arranged to couple efficiently said radiation between said fiber andthe biological tissue region.
 8. The optical system of claim 1 whereinsaid array of optical fibers is arranged as an irradiation array withsaid proximal ends optically coupled to a light source of saidspectrophotometer.
 9. The optical system of claim 1 wherein said arrayof optical fibers is arranged as a detection array with said proximalends optically coupled to a light detector of said spectrophotometer.10. The optical system of claim 1 wherein said spectrophotometer isfurther constructed and arranged for imaging of the brain.
 11. Theoptical system of claim 1 wherein said spectrophotometer is a continuouswave spectrophotometer.
 12. The optical system of claim 1 wherein saidspectrophotometer is a phase modulation spectrophotometer.
 13. Theoptical system of claim 1 wherein said spectrophotometer is a timeresolved spectrophotometer.
 14. The optical system of claim 1 whereinsaid spectrophotometer is a phased array spectrophotometer.
 15. Anoptical system for in vivo examination of biological tissue,comprising:a spectrophotometer constructed and arranged to generateoptical radiation of at least one visible or infra-red wavelength andcharacterize biological tissue by detecting photons of said wavelengththat have migrated in the tissue, a first array of optical fibersincluding proximal ends optically coupled to a light source of saidspectrophotometer, and distal ends freely protruding from a support inthe manner of bristles from a hairbrush and forming an array of opticalinput ports constructed and arranged to introduce said optical radiationinto an input region of the biological tissue, and a second array ofoptical fibers including proximal ends optically coupled to provide saidradiation to a light detector of said spectrophotometer, and distal endsfreely protruding from said support in the manner of bristles from ahairbrush and forming an array of optical detection ports constructedand arranged to collect said optical radiation that has migrated in thebiological tissue from said input region to a detection region.
 16. Theoptical system of claim 15 wherein said first and second arrays areconstructed to examine a selected tissue volume, said first array beingconstructed to introduce said radiation into said input region, and saidsecond array being constructed to collect said radiation that hasmigrated in said volume to said detection region being spaced apart fromsaid input region by a selected distance.
 17. The optical system ofclaim 16 further comprising:a third array of optical fibers includingproximal ends optically coupled to a light source of saidspectrophotometer, and distal ends freely protruding from a secondsupport in the manner of bristles from a hairbrush and forming an arrayof optical input ports constructed and arranged to introduce saidradiation into a second input region, and a fourth array of opticalfibers including proximal ends optically coupled to provide saidradiation to a light detector of said spectrophotometer, and distal endsfreely protruding from said second support in the manner of bristlesfrom a hairbrush and forming an array of optical detection portsconstructed and arranged to collect said radiation that has migrated inthe biological tissue to a second detection region being spaced apartfrom said second input region by said distance.
 18. The optical systemof claim 15 wherein said biological tissue is brain tissue.
 19. Theoptical system of claim 18 wherein said distal ends of at least some ofsaid optical fibers are sized and distributed to penetrate freelyextending hair on the head of a subject to make optical contact directlyover said localized tissue region with a surface of the scalp or skinbelow said hair.
 20. A method of in vivo examination of human tissuecomprising:providing an array of optical fibers constructed and arrangedto transmit optical radiation in a visible to infra-red range between aspectrophotometer and biological tissue, wherein said optical fibers ofsaid array are freely protruding from at least one support in the mannerof bristles from a hairbrush; generating radiation of said wavelengthfrom a light source of said spectrophotometer, introducing saidradiation from distal ends of said fibers into an input region of thebiological tissue, collecting photons that have migrated from said inputregion to a detection region of the examined tissue, detecting saidradiation that has migrated in the biological tissue, and examining saidtissue by processing signals of said detected radiation.